Ezetimibe is a known representative of these compounds which blocks the absorption of cholesterol from the intestine, so that both lower LDL levels and fewer triglycerides are observed in patients. Specifically, the compound is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone of the following formula (see claim 8 in EP 0 720 599 B1).

Knowing this compound per se, there are also known to exist some chemical modifications, as well as their preparation by various process variants and their therapeutic use for the treatment of hyperlipidemia and of arteriosclerosis and hypercholesterolemia, inter alia the following publications have appeared, attempts having been made for example to define chemical modifications of comparable therapeutic effect but with less intestinal absorption.
EP 0 524 595 A1 describes chemical modifications of ezetimibe of the formula
which may inter alia also have a second substituent (R2) in position 3 of the azetidinone ring, also have connecting moieties (A) between the phenyl ring in position 4 of the azetidinone ring and the ring, and have no or other substituents instead of the fluorine groups on the phenyl rings (R3, R4).
The compounds are synthesized (e.g. for R2=H) either by cyclization of hydroxy amides of the formulae
with, for example, trialkylphosphine/dialkyl azodicarboxylate, a phase-transfer catalyst, dialkyl chlorophosphate/tetra-n-butylammonium hydrogen sulfate or dichlorobenzoyl chloride/NaH, orby reaction of esters (Rx is, for example alkyl) of the following formula with imines in the presence of strong bases
orby a comparable reaction, but with a different carboxylic acid derivative, e.g. an acid chloride or mixed anhydride (in which case 2-oxy-N-methylpyridinium iodide for example instead of ORx), orby modifying the preparation of the above hydroxy amides in the (precursor) stage of the compound of the formula
(Ry, Rz are, for example, independently of one another H, (C1-C6)alkyl, phenyl, benzyl) by reaction with one of the imines R1-A-CH═N—R4 defined above in the presence of TiCl4 and TMEDA (tetramethylethylenediamine) to give
and further reaction with Na bis-trimethylsilylamide or Li bis-trimethylsilylamide to give
EP 0 707 567 B1 discloses a specific process for preparing azetidinone derivatives of this type in which (Q=H or, for example, alkyl)
β-(substituted amino) imides of the above formula, which are protected in a suitable way, where G- is selected from the group comprising one of the following radicals,
which are reacted with a silylating agent and a fluoride ion catalyst as a cyclizing agent or with a salt of the chiral compound (G+ salt), in particular with bis(trimethylsilyl)acetamide and tetra-n-butylammonium fluoride.
Further compound modifications of diphenylazetidinone derivatives are described for example in WO 02/50027 which is hereby incorporated by reference, wherein at least one of the substituents on the three (3) phenyl radicals present in the molecule is a (C1-C30)alkylene-(LAG) radical in which one or more carbon “C” atoms of the alkylene radical may be replaced by, for example, —O—, —CH═CH— or —NR— [R=H, (C1-C6)alkyl, (C1-C6)alkylene-phenyl], and LAG is for example a saccharide, disaccharide, trisaccharide, amino acid or oligopeptide residue.
One disadvantage of this process is the use of large amounts of silylating agents such as N,O-bis(trimethylsilyl)acetamide, because acetamide is produced during the reaction and is classified as carcinogenic. In addition, the diastereoselectivity during the addition reaction stage by using enolate and imine tends to be moderate, making additional separation stages necessary.
It is an object of the invention to indicate a further synthesis variant for the aforementioned compounds, which can also be carried out stereospecifically and in high yield, by requiring auxiliary reagents which have minimal toxicity so that it does not give rise to major problems at the workplace when also implemented industrially.